1. Field of the Invention
The present invention relates to the use of stem cell factor in association with interleukin-6 and soluble interleukin-6 receptor to induce the development of hematopoietic stem cells. More particularly, the present invention involves the combined use of these factors to promote the production of erythroid cells.
2. Description of the Background
Interleukin-6 (IL-6) is a cytokine that appears to be one of the mediators of the response to viral and bacterial infections and to shock. The purification, cloning and use of IL-6 has been reported (EP 220 574, published May 6, 1987, Revel et al.; WO 88/00206, published Jan. 14, 1988, Clark et al.). It has also been reported that gp130, which is a second receptor molecule of IL-6 (as well as oncostatin M, ciliary neurotrophic factor and IL-11), is expressed on the surface of a wide variety of cells. In addition, an extracellular soluble form of the interleukin-6 receptor (sIL-6R) can associate, when occupied by IL-6, with membrane-anchored gp130 and thereby activate cellular signaling processes (8-10). The purification and cloning of soluble IL-6 receptor have been reported, as has its combined use with IL-6 in conditions such as bacterial infections, burns and trauma (EP 413 908, published Feb. 27, 1991, Novick et al.).
Stem cell factor (SCF) is an early acting hematopoietic factor. The purification, cloning and use of SCF have been reported (see PCT WO 91/05795, entitled "Stem Cell Factor"). The use of SCF has been described for enhancing engraftment of bone marrow and bone marrow recovery as well as for the treatment of leukopenia and thrombocytopenia. The use of SCF in combination with IL-6 has been described, but there are no previous reports of the combined use of SCF, IL-6 and soluble IL-6 receptor.
Erythropoiesis, the production of red blood cells, occurs continuously to offset cell destruction. Erythropoiesis is a precisely controlled physiological mechanism enabling sufficient numbers of red blood cells to be available for proper tissue oxygenation, but not so many that the cells would impede circulation. The formation of red blood cells occurs in the bone marrow and is under the control of the hormone, erythropoietin. It is generally accepted that erythropoietin is the primary humoral regulator of erythropoiesis and that it is the single factor which supports the proliferation and terminal maturation of erythroid cells from hematopoietic stem cells (1-4). Erythropoiesis has been extensively studied, and there have been no previous descriptions of the physiological regulation of erythropoiesis by a pathway other than erythropoietin signaling.